In the chemical modifications of cephalosporin antibiotics, another type of substitution at carbon atom C-2 of the 3-cephem moiety was discovered when a cephalosporin was reacted under Mannich conditions to give a product which did not contain the usual .beta.-substituted amino group of the normal Mannich reaction products. The identification of a methylene group at C-2 indicated that the expected amino group had been eliminated under reaction conditions. The cephalosporin exocyclic methylene at C-2 was found to undergo certain addition reactions. Bromine and thiols were added under mild conditions. However, amines or alcohols did not add to the double bond under the conditions studied.
It has been found that certain carbanions will undergo a Michael type addition with 2-methylene-3-cephem sulfoxides to provide novel cephalosporin Michael adducts which have antibiotic properties.
It is an object of this invention to provide antibiotic 7-acylamino-2-(substituted ethyl)-3-cephem-4-carboxylic acids which are prepared with the 2-methylene cephalosporins available by the method of Wright, et al., J. Med. Chem., 14, 420 (1971).
In the chemical modification of cephalosporins, it is often desirable to cleave the 7-carboxamido group to obtain a free amino group in the 7-position. One method of cleaving an amido group to obtain the free amine is that described by Lander, J. Chem. Soc., 83, 320 (1903). In accordance with Lander's method the amide is treated with a halogenating agent to convert the amido group to an imino halide and the imino halide is treated with an alcohol to obtain the imimo ether which is then hydrolyzed to the free amine. The application of this method to the cleavage of cephalosporin C to 7-aminocephalosporanic acid (7-ACA) is disclosed in Canadian Pat. No. 770,125 and British Pat. No. 1,041,985.
Cleavage of the carboxamido group of the 7-acylamino-2-(substituted ethyl) cephalosporins of this invention provides the 7-amino-2-(substituted ethyl)-3-cephem compounds described herein. Such a cephalosporin Michael adduct "nucleus" is useful for generating further 7-acylamino-2-(substituted ethyl) cephalosporins of this invention.